The Paramyxoviridae family is a family of single stranded RNA viruses in the order Mononegavirales. Genera of the Paramyxoviridae family include Paramyxovirus, Pneumovirus, Morbillivirus, Rubulavirus, and Henipavirus. These viruses can be transmitted person to person via direct or close contact with contaminated respiratory droplets or fomites. The Henipavirus genus includes the species Cedar virus, Hendra virus and Nipah virus. The Metapneumovirus genus includes the human metapneumovirus. The Morbillivirus genus includes the species measles virus. The Respirovirus genus includes the Sendai virus and the human parainfluenza viruses 1 and 3. The Rubulavirus genus includes the mumps virus and the human parainfluenza viruses 2 and 4. The Pneumovirus genus includes respiratory syncytial virus (RSV).
RSV is a nonsegmented negative-strand (NNS) RNA virus that can cause respiratory infections and is associated with bronchiolitis and pneumonia. The virus can be the cause of infections in bone marrow as well as solid organ transplant patients, cystic fibrosis patients and congenital heart disease patients, and is increasingly being recognized as the cause of respiratory tract disease in elderly, non-immunocompromised adults. There are currently two known strains of RSV: the A strain and the B strain.
As with most Paramyxoviridae, RSV is transmitted person to person via direct or close contact with contaminated respiratory droplets or fomites. Symptoms of an RSV infection include coughing, sneezing, runny nose, fever, decreased appetite, and wheezing. RSV is the most common cause of bronchiolitis and pneumonia in children under one year of age in the world. In addition, RSV can be the cause of tracheobronchitis in older children and adults. Worldwide, sixty four million people are infected annually with RSV, resulting in up to 200,000 deaths. In the United States, it is estimated that between 75,000 and 125,000 infants are hospitalized each year with RSV. In addition, among adults over the age of sixty five, an estimated 14,000 deaths and 177,000 hospitalizations are attributed to RSV each year.
Treatment options for people infected with RSV are currently limited. There is no reliable vaccine against RSV despite work spanning over forty years. While antibiotics typically prescribed to treat bacterial infections and over-the-counter medications may relieve some RSV symptoms, they are not effective in treating the virus itself In severe cases, a nebulized bronchodilator, such as albuterol, may be prescribed to relieve symptoms such as wheezing. RespiGram® (RSV-IGIV, Medimmune, approved for high risk children younger than 24 months of age), Synagis® (palivizumab, Medimmune, approved for high risk children younger than 24 months of age), and Virzole® (ribavirin by aerosol, ICN pharmaceuticals) have been approved for the treatment of RSV.
Palivizumab, a prophylactically administered humanized anti-RSV fusion protein monoclonal antibody is the most widely used preventive therapy against RSV for premature and high-risk infants. Ribavirin must be administered by small-particle aerosol for 12-18 h per day for 3-7 days. The drug is only marginally effective against RSV and is not indicated in adults. See, Dunn et al., “Inhibition of respiratory syncytial virus in vitro and in vivo by the immunosuppressive agent leflunomide”, Antiviral Ther., 16, 309-317, 2011.
The Orthomyxoviridae are a family of RNA viruses that includes six genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus, Quaranjavirus, and Thogotovirus. The first three genera contain viruses that cause influenza in vertebrates, including birds (see also avian influenza), humans, and other mammals. Influenzavirus A has been further classified into types based on the viral surface proteins: hemagglutinin (H or HA) and neuraminidase (N). There are approximately 16 H antigens (H1 to H16) and 9 N antigens (N1 to N9). Influenza A includes several subtypes including: H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, H10N7. Isaviruses infect salmon; thogotoviruses infect vertebrates and invertebrates, such as mosquitoes and sea lice.
Influenza is mainly spread from person to person by droplet infection or droplet nuclei created by sneezing, coughing or talking. The port of entry of the virus is the respiratory tract. Complications from an influenza viral infection include pneumonia, bronchitis, dehydration, and sinus and ear infections. Medications currently approved by the FDA for the treatment of an influenza infection include amantadine, Relenza® (zanamivir, GlaxoSmithKline), Rapivab® (peramivir, BioCryst Pharmaceuticals, Inc.), rimantadine, and Tamiflu® (oseltamivir, Genentech).
The RSV non-structural protein RNA-dependent RNA polymerase is a key enzyme responsible for initiating and catalyzing viral RNA synthesis. As a result, RSV RNA-dependent RNA polymerase is an attractive target for the current drug discovery and development of anti-RSV agents. In general, there are two major subclasses of RNA-dependent RNA polymerase inhibitors: nucleoside analogs, which are anabolized to their active triphosphates—which act as alternative substrates for the polymerase—and non-nucleoside inhibitors (NNIs), which bind to allosteric regions on the protein. Nucleoside or nucleotide inhibitors mimic natural polymerase substrates and act as chain terminators. They inhibit the initiation of RNA transcription and elongation of a nascent RNA chain.
In 1976, Moffatt et al. reported on the synthesis of the nucleoside antibiotic nucleocidin; see structure below:

The structure of nucleocidin was unique in that it was the first natural product to contain either a fluoro carbohydrate or an unsubstituted sulfamoyl group. In addition, it appeared to be the first example of a furanose sugar bearing a functional substituent at the 4′-position, see, “4′-Substituted Nucleosides. 2. Synthesis of the Nucleoside Antibiotic Nucleocidin”, Moffatt, J. G. et al., J. Am. Chem. Soc., 98(11)3346-3357, 1976. Moffatt et al. also reported on the synthesis of 4′-fluorouridine derivatives, see, “4′-Substituted Nucleosides. 3. Synthesis of Some 4′-Fluorouridine Derivatives”, Owens, G. R., et al., J. Org. Chem., 41(18)3010-3017, 1976.
Patents and patent applications describing nucleosides and nucleotides include WO 1998/016184; WO 1998/016186; WO 2002/100415; WO 2003/073989; U.S. 2004/0229839; US; WO 2005/009418; WO 2005/020884; WO 2005/021568; WO 2006/000922; WO 2006/094347; WO 2007/113538; WO 2008/117047; WO 2008/117046; WO 2008/121634; WO 2009/152095; WO 2009/132135, WO 2012/012776; U.S. 2016/0176910; and U.S. Pat. Nos. 7,964,580; 8,173,621; 8,334,270; 8,580,765; 8,735,372; 8,759,510; 8,906,880; 8,957,046; 9,085,573; 5,420,115; 9,073,960, 9,441,007; 7,429,572; 9,422,322; 7,138,376; 9,187,515; and, 9,211,300.
Additional patent and patent applications include WO 2010/002877; WO 2010/030858; WO 2010/091386; WO 2010/108135; WO 2010/108140; WO 2011/035231; U.S. 2012/0009147; U.S. 2012/0071434; U.S. Pat. No. 8,877,731; WO 2012/012465; WO 2012/037038; U.S. Pat. No. 9,073,960; WO 2013/019874; WO 2013/092481; WO 2013/138236; U.S. 2014/0309413; WO 2014/070771; WO 2014/079903; WO 2014/100505; U.S. 2015/0366888; WO 2016/041877; U.S. 2016/0016986 U.S. Pat. No. 9,296,777; WO 2016/188943; WO 2016/069975; WO 2015/081133; and, U.S. 2016/0257706.
As the treatment options for people infected with viruses of the Paramyxoviridae and Orthomyxoviridae families are limited, there remains a strong medical need to develop anti-Paramyxoviridae and anti-Orthomyxoviridae therapies that are safe, effective and well-tolerated. The need is accentuated by the expectation that drug resistance can arise, as seen in anti-HIV and anti-HCV therapies, and new combination drug therapies may be needed to treat viruses of the Paramyxoviridae and Orthomyxoviridae families. More potent direct-acting antivirals could significantly shorten treatment duration and improve compliance and SVR rates for patients infected with viruses of the Paramyxoviridae and Orthomyxoviridae families.
It is therefore an object of the present invention to provide compounds, pharmaceutical compositions, and methods to treat or prevent infections by viruses of the Paramyxoviridae and Orthomyxoviridae families.